Alzheimer's disease (AD) is the major age-related dementia, and is expected to take an increasing toll on society as the population ages. Histopathologically, while the diagnostic criterion for AD is the presence of amyloid-containing plaques and neurofibrilliary tangles, AD brains are typified by increased oxidative stress and focal neuronal death. While the exact relationship between beta amyloid (AP) deposition, oxidative stress, and neuronal injury is still unresolved, increasing evidence suggests that the NADPH oxidase system may be altered in AD and in response to Ap. NADPH oxidase (NOX), originally described as the main component of the leukocyte oxidative burst, produces reactive oxygen species (ROS) that are involved in both intracellular signaling and oxidative stress. NOX expression has been established in neurons, thus raising the possibility that aberrant activation of neuronal NOX by toxic forms of A(3 could contribute to ADrelated neuronal alterations. The focus of this project is to test the hypothesis that sustained activation of NOX by Ap triggers a pernicious cascade linking increases in ROS production to altered intracellular redoxbased signaling and oxidative stress, culminating in neuron degeneration and death. The specific aims to test this hypothesis are as follows: 1) To test the hypothesis that NOX activity is increased during the progression of AD; 2) To test the hypothesis that NOX activity is increased in response to increasing Ap deposition in a specific APP/PS1 knock-in mouse model of amyloidogenesis; 3) To test the hypothesis that toxic forms of Ap increase neuronal oxidative stress and cell death via NOX; 4) To test the hypothesis that microglial NOX activation exacerbates neuronal responses to AP; and 5) To test the hypothesis that genetic or pharmacologic ablation of NOX in the APP/PS1 transgenic mice attenuates oxidative stress and Ap pathogenesis in vivo. The proposed experiments will make use of our extensive and well-characterized tissue bank of human brain specimens, as well as a novel and highly relevant mouse model of beta amyloid pathogenesis. Finally, studies will determine the specific effects of distinct physiological forms of AP(1-40/1- 42/oligomer/fibrillar) on NOX activation both in vitro and in vivo. Completion of these studies will result in a more thorough understanding of the relationship between Ap deposition and AD-related neuronal pathology, and could highlight an innovative and highly promising target for therapeutic intervention in AD.